Cocaine use disorders are an unrelenting public health concern. Intensive research efforts have yielded behavioral interventions that reduce cocaine use, however, these interventions are not universally effective and treatment effects diminish over time. Development of a pharmacotherapy that enhances the efficacy of these interventions is a priority for the National Institute on Drug Abuse. In the central nervous system cocaine blocks the reuptake and induces release of dopamine and serotonin, thus a successful cocaine pharmacotherapy will likely need to target both of those neurotransmitters. Buspirone, an anxiolytic medication with limited abuse potential, is an antagonist at dopamine autoreceptors and a partial agonist at serotonin 5- HT1A receptors; both of these receptors play crucial roles in the abuse-related effects of cocaine. Dopamine autoreceptors stabilize dopaminergic tone and antagonists at these receptors can increase dopamine release. Moreover, medications with partial agonist activity have been recognized as valuable tools for managing opioid and nicotine use disorders due to their ability to stimulate receptors when neurotransmitter tone is low (i.e., during abstinence) and block receptors when neurotransmitter tone is high (i.e., following a lapse). Although buspirone produces pharmacological effects that are likely beneficial for treating cocaine dependence, we are unaware of any human laboratory research that has tested the influence of buspirone on the behavioral effects of cocaine, a notable gap in the literature considering that such research can efficiently screen potential medications prior to the conduct of large-scale clinical trials. This study will assess the reinforcing, subject- rated, cognitive, performance and physiological effects of cocaine during maintenance on buspirone. By determining how buspirone impacts the behavioral effects of cocaine, we will provide important evidence regarding the potential efficacy of this compound for managing cocaine use disorders. These results will help to broaden the current clinical neuroscience paradigm of cocaine medications development efforts beyond a focus on dopamine systems. In addition, demonstrating the initial efficacy of a commercially available drug will impact clinical research more quickly than waiting for novel molecules to be available for testing in humans. PUBLIC HEALTH RELEVANCE: A successful pharmacological adjunct for managing cocaine use disorders will likely need to target more than the dopamine system. Buspirone, an anxiolytic with limited abuse potential, is a serotonin 5HT1A receptor partial agonist and dopamine autoreceptor antagonist that may be effective in treating cocaine dependence. This project will test the influence of buspirone maintenance on the reinforcing effects of cocaine in the human laboratory to further demonstrate its potential efficacy in cocaine use disorders.